Parkinsonism and dystonia are crippling and sometimes fatal disorders affecting millions of people. The pathogenesis of these disorders is still a mystery. X-linked dystonia-parkinsonism (XDPD) is a rare condition with dystonia and parkinsonism. The co- occurrence of dystonia and parkinsonism in XDPD and other disorders suggests they may have common pathogenetic mechanisms. Insight gained by studying XDPD may have importance beyond the few people who suffer from this condition. Histologic and physiologic data suggest XDPD is the result of preferential degeneration of the striatum. Identification of the genetic defect in this disease may provide an important clue toward understanding the pathogenesis and pathophysiology of both dystonia and parkinsonism, and other degenerative diseases of the nervous system. Unlike Parkinson's disease, XDPD has a simple pattern of inheritance (X-linked recessive). Because of its simple mode of inheritance, XDPD is a good candidate for study with genetic tools. The XDPD disease locus, XDPD (X-linked dystonia-parkinsonism, "DYT3" in the Human Genome Database), is in the Xq13 region. There is extreme linkage disequilibrium between XDPD and a haplotype based on eighteen microsatellite polymorphisms spanning the region. Since all of our patients with XDPD have ancestors from the Phillipines and >76% have elements of a putative founder haplotype, we believe most patients with XDPD have a common ancestor. Preliminary haplotype data suggest that XDPD can be localized to a region of much less than one centimorgan, and possibly less than O.2cM. The goal of this project is to isolate the XDPD gene by positional cloning. We will map XDPD more precisely by further haplotype analysis. This region will be physically mapped and cloned. We will find the gene by studying the transcription and sequence of candidate genes in normal and affected individuals. We will then begin to study the physiologic function of this sequence and determine if the mechanisms involved in XDPD are related to other neurodegenerative diseases.